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    Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for <em>Drosophila</em> NF-кB Signaling: A Dissertation

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    Authors
    Paquette, Nicholas Paul
    Faculty Advisor
    Neal Silverman, Ph.D.
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2009-11-03
    Keywords
    Immunity
    Innate
    I-kappa B Kinase
    Drosophila Proteins
    Bacterial Proteins
    Yersinia pestis
    Amino Acids, Peptides, and Proteins
    Animal Experimentation and Research
    Bacteria
    Enzymes and Coenzymes
    Hemic and Immune Systems
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    Abstract
    Innate immunity is the first line of defense against invading pathogens. Vertebrate innate immunity provides both initial protection, and activates adaptive immune responses, including memory. As a result, the study of innate immune signaling is crucial for understanding the interactions between host and pathogen. Unlike mammals, the insect Drosophila melanogasterlack classical adaptive immunity, relying on innate immune signaling via the Toll and IMD pathways to detect and respond to invading pathogens. Once activated these pathways lead to the rapid and robust production of a variety of antimicrobial peptides. These peptides are secreted directly into the hemolymph and assist in clearance of the infection. The genetic and molecular tools available in the Drosophila system make it an excellent model system for studying immunity. Furthermore, the innate immune signaling pathways used by Drosophilashow strong homology to those of vertebrates making them ideal for the study of activation, regulation and mechanism. Currently a number of questions remain regarding the activation and regulation of both vertebrate and insect innate immune signaling. Over the past years many proteins have been implicated in mammalian and insect innate immune signaling pathways, however the mechanisms by which these proteins function remain largely undetermined. My work has focused on understanding the molecular mechanisms of innate immune activation in Drosophila. In these studies I have identified a number of novel protein/protein interactions which are vital for the activation and regulation of innate immune induction. This work shows that upon stimulation the Drosophila protein IMD is cleaved by the caspase-8 homologue DREDD. Cleaved IMD then binds the E3 ligase DIAP2 and promotes the K63-polyubiquitination of IMD and activation of downstream signaling. Furthermore the Yersinia pestis effector protein YopJ is able to inhibit the critical IMD pathway MAP3 kinase TAK1 by serine/threonine-acetylation of its activation loop. Lastly TAK1 signaling to the downstream Relish/NF-κB and JNK signaling pathways can be regulated by two isoforms of the TAB2 protein. This work elucidates the molecular mechanism of the IMD signaling pathway and suggests possible mechanisms of homologous mammalian systems, of which the molecular details remain unclear.
    DOI
    10.13028/pc1q-pe08
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31773
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/pc1q-pe08
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